Growing evidence from our group and others indicates that the amygdala and the entorhinal cortex play an important role in the pathogenesis of major psychoses. Adding to this evidence, recent results from our group point to abnormalities of the extracellular matrix (ECM) molecules chondroitin sulfate proteoglycans (CSPGs) in medial temporal lobe regions of subjects with schizophrenia. The large effect size and widespread distribution of these changes suggest that CSPGs may play a crucial, and previously unsuspected, role in the pathogenesis of schizophrenia. Numbers of glial cells labeled with wisteria floribunda agglutinin (WFA), putatively expressing CSPGs, were found to be markedly increased in the basolateral-cortical complex of the amygdala (BLC-CO) and in the ECx of subjects with SZ. These changes were accompanied by decreased numbers of perineuronal nets (PNNs), mesh-like pericellular condensations of ECM enriched in CSPGs. The postmortem, stereology-based, immunocytochemical investigations proposed here are based on these findings. Specific Aim 1 is designed to test the following hypotheses: a) Numbers of glial cells expressing distinct members of the CSPG group of molecules are increased in the BLC-CO and ECx of subjects with SZ; b) Numbers of CSPG-immunoreactive PNNs will be reduced in the same regions; c) These changes are not accompanied by astrogliosis; d) No changes will be detected in subjects with BD. Specific Aim 2 will address the hypothesis that abnormalities similar to those occurring in the BLC-CO and ECx are also present in other medial temporal lobe regions, i.e. the central and medial nuclei of the amygdala, perirhinal cortex, pre-/para- subiculum and subiculum. Tissue blocks from a cohort of normal control (n=15), SZ (n=15) and BD (n=15) subjects is available for these studies. The identification of the specific CSPGs altered in schizophrenia represents a fundamental step toward understanding the role of ECM molecules in the pathogenesis of this disease. CSPGs play a broad range of functions in the developing and adult brain, including regulation of neuronal migration, axonal growth, synaptic plasticity, glutamatergic and GABAergic transmission. These functions are resonant with the pathophysiology of schizophrenia and may underlie several of its critical aspects. The occurrence of CSPG-related changes in a set of interconnected medial temporal lobe regions widely thought to represent a core neural circuit in the pathophysiology of SZ adds to their relevance. Moreover, the disease-specificity of CSPG abnormalities may be key to our understanding of pathophysiological and pharmacological differences between these schizophrenia and bipolar disorder. In summary, the relevance of the proposed studies resides in their potential of uncovering an as yet unknown and distinctive aspect of the pathophysiology of SZ, involving altered ECM functions in regions of medial temporal lobe known to play an important role in this disease.PUBLIC HEALTH RELEVANCE: Despite growing evidence supporting the involvement of the amygdala and entorhinal cortex in major psychoses, very little is known with regard to their specific pathophysiology. The relevance of investigations on these brain regions resides in their functional role, linking emotional and cognitive processing, and in recent findings pointing to substantial, yet unexpected, abnormalities affecting the extracellular matrix in the amygdala and entorhinal cortex of subjects with schizophrenia. The proposed studies will provide potentially critical information needed to improve our understanding of these two disorders and their pharmacological treatment. [unreadable] [unreadable] [unreadable]